We previously generated DT40 cells in which both alleles of the SIRT6 gene were inactivated by gene targeting, and tested the sensitivity of these cell lines towards DNA damaging agents. In contrast to previous reports in murine embryonic stem cells, no defects in DNA repair could be identified in this B-cell line. Gene expression microarray data indicated, however, that SIRT6 is important for the control of global gene expression. Hundreds of genes were misregulated, and chromatin immunoprecipitation (ChIP) experiments link this observation to changes in histone acetylation patterns. The identification of primary targets of SIRT6 by ChIP-Sequencing are currently analyzed. These findings are consistent with a recent report of SIRT6 being important for the activation of NFkappaB target genes. Overall we expect to gain insight into the genetic pathways that are controlled by SIRT6, and how this contributes to controlling responses to stimuli (including stress) and ultimately regulating organismal lifespan. In addition, we started a collaboration to identify small molecule compounds that can regulate SIRT6 enzyme activity in vitro and in vivo.